In present investigation, the in vitro antioxidant activities of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV) were studied in DPPH, hydroxyl radical, reducing power, and ferrous ion-chelating models. In DPPH and reducing power model, the phenolic hydroxyl group of ODV contributed to the antioxidant capacities, where the antioxidant activities of ODV was better than that of VEN. In hydroxyl radical and ferrous ion-chelating models, the antioxidant capacities of ODV was equal or somewhat inferior to that of VEN, which indicated that the phenolic hydroxyl contributed a little in these in vitro antioxidant models. The current results might provide certain proofs to obtain the insight of action mechanisms of VEN and ODV.